FDA Panel Gives Nod to Overactive Bladder Drug

WASHINGTON -- An FDA advisory committee has voted 7-4, with one member abstaining, that the benefits of the overactive bladder drug mirabegron outweigh its risks.

The FDA's Reproductive Health Drugs Advisory Committee voted Thursday afternoon that although mirabegron offered only a "marginal" benefit compared with placebo it gives a new option to reduce frequent urination and to control urination for patients suffering from overactive bladder (OAB).

On another question, the panel voted 8-4 that mirabegron is effective, but nearly every panelist expressed doubts at just how effective it is, pointing out that only 7% of patients on mirabegron had a substantial improvement in OAB symptoms compared with placebo.

"I voted yes, but I had substantial reservations," said panelist Stuart Howards, MD, a urologist with the University of Virginia in Charlottesville. "Although this is statistically significant, it's a pretty marginal clinical benefit over placebo."

Mirabegron, made by Astellas, selectively binds and activates beta-3 adrenoreceptors on the bladder muscle, which helps to facilitate filling and storage. It's a novel mechanism for a bladder control drug. The current standard is a class of drugs called antimuscarinics, which can cause such side effects as severe dry mouth and constipation, leading many patients to discontinue their use.

The advisory panel based its decisions on data from three 12-week, randomized, placebo-controlled trials, in which treatment with 50 mg of mirabegron once a day showed a reduction of incontinence episodes and urination over 24 hours as compared with placebo (P<0.001 for both).

Patient-reported outcomes -- including treatment satisfaction, bothersome symptoms, and OAB-specific health-related quality of life -- also improved significantly in the mirabegron groups compared with the placebo groups (P<0.05 for each).

In documents released in advance of the meeting, FDA staff reviewers raised serious concerns with the safety of the drug, in particular its effect on blood pressure, heart rate, and liver function. However, the panel seemed to think those safety risks could be managed and voted 9-3 that mirabegron is safe.

Compared with the placebo group, patients taking mirabegron experienced an increase in blood pressure of about 1 mm Hg from baseline in systolic and diastolic blood pressures and an increase of approximately 1 beat per minute in heart rate.

There were also three reports of severe hepatotoxicity in patients taking mirabegron, which "appear to reflect a rare potential for mirabegron to adversely affect liver function," the FDA reviewers wrote.

In addition, there were reports of hypersensitivity reactions (including one case of Stevens Johnson syndrome), urinary tract-related adverse events (UTI and renal colic), a variety of neoplasms, and glaucoma and increases in intraocular pressure reported in the mirabegron group of the clinical trails.

Panelist Christian Pavlovich, MD, a urologic oncologist at Johns Hopkins Bayview Medical Center, said the slight increases in blood pressure and heart rate could be managed, and the hepatotoxicity and hypersensitive side effects are similar to what's seen in other bladder control drugs in use.

Another panelist, Marc Garnick, MD, a professor of medicine at Harvard, voted that mirabegron has not been shown to be safe.

"The bar really has to be quite high for a product that has the potential to be used in millions of patients," he said, adding that he was especially concerned about the increased rate of neoplasms.

An estimated 34 million people in the U.S. suffer from OAB. The FDA does not have to follow the advice of its advisory committees, but it often does.

If the drug is approved, all panelists agreed, there should be ongoing studies to monitor safety signals.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

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